CCL18: a potential immunosuppressive biomarker for prognosis in ABC diffuse large B-cell lymphoma.

Background: Activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) has worse outcomes than the germinal center B-cell (GCB) subtype, but underlying molecular mechanisms remain poorly understood. Methods: Transcriptomic analysis on 43 DLBCL samples (23 GCB and 20 ABC) was performed using NanoString PanCancer Immune Profiling Panel with 30 cell-of-origin genes. Tumor microenvironment characterization was performed using CIBERSORTx and gene set enrichment analysis (GSEA) deconvolution. Based on our previous findings of MAPK10 downregulation in ABC lymphomas, MAPK10 promoter methylation was studied via pyrosequencing. Prognostic biomarkers were identified using the Cox regression and least absolute shrinkage and selection operator (LASSO) regularization. Therapeutic candidates were identified through connectivity mapping. Results: ABC lymphomas showed distinct profiles with the overexpression of VTCN1, CDK4, and CXCR5 and the downregulation of MMP9 and MAPK10. GSEA revealed enrichment of inflammatory pathways with immunosuppressive signals in ABC cases. Confirming our prior observations, MAPK10 downregulation in ABC tumors was associated with promoter hypermethylation and inferior overall survival (p < 0.01). Immune deconvolution revealed greater microenvironmental diversity in ABC cases with significant eosinophil enrichment. High CD8+ T-cell abundance was associated with improved survival, particularly in ABC patients (p < 0.01). Multivariate analysis identified CCL18 as an independent adverse prognostic factor (HR: 1.87, 95% CI: 1.25-2.79, p < 0.01). Connectivity mapping identified proteasome inhibitors and CDK4/6 inhibitors as promising therapeutic candidates. Conclusions: We validated MAPK10 promoter hypermethylation and CCL18 overexpression as prognostic biomarkers in ABC DLBCL. These findings, derived from integrative transcriptomic and immunogenomic profiling, provide clinically relevant insights into disease biology and support biomarker-guided strategies for precision treatment in aggressive B-cell lymphomas.